Molecular Genetics, Structure-Function Relationships, and Tissue-Specific Expression and Regulation of the 3βHSD Gene Family

Labrie, Fernand; Simard, Jacques; Luu‐The, Van; Pelletier, Georges

doi:10.1007/978-1-4612-2638-3_7

Cited by 1 publication

(1 citation statement)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It should be noted that the catalytic efficiency of human type I 3␤-HSD is 5.9-, 4.5-, and 2.8-fold higher than the catalytic efficiency (V max /K m ) of the human type II 3␤-HSD (adrenal/gonadal) isoform using PREG, DHEA, and DHT, respectively, as substrates (27). The higher K m for type II 3␤-HSD is correlative to the higher amounts of substrate produced in these tissues (430). A detailed understanding of the regulation of 3␤-HSD in the placenta and other peripheral tissues must take into consideration the catalytic differences between the two isoforms present in humans.…”

Section: Placentamentioning

confidence: 99%

Molecular Biology of the 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase Gene Family

et al. 2005

Self Cite

View full text Add to dashboard Cite

The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase (3beta-HSD) isoenzymes are responsible for the oxidation and isomerization of Delta(5)-3beta-hydroxysteroid precursors into Delta(4)-ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. In humans, expression of the type I isoenzyme accounts for the 3beta-HSD activity found in placenta and peripheral tissues, whereas the type II 3beta-HSD isoenzyme is predominantly expressed in the adrenal gland, ovary, and testis, and its deficiency is responsible for a rare form of congenital adrenal hyperplasia. Phylogeny analyses of the 3beta-HSD gene family strongly suggest that the need for different 3beta-HSD genes occurred very late in mammals, with subsequent evolution in a similar manner in other lineages. Therefore, to a large extent, the 3beta-HSD gene family should have evolved to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids, and cytokines. Recent studies indicate that HSD3B2 gene regulation involves the orphan nuclear receptors steroidogenic factor-1 and dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1). Other findings suggest a potential regulatory role for STAT5 and STAT6 in transcriptional activation of HSD3B2 promoter. It was shown that epidermal growth factor (EGF) requires intact STAT5; on the other hand IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. However, evidence suggests that multiple signal transduction pathways are involved in IL-4 mediated HSD3B1 gene expression. Indeed, a better understanding of the transcriptional factors responsible for the fine control of 3beta-HSD gene expression may provide insight into mechanisms involved in the functional cooperation between STATs and nuclear receptors as well as their potential interaction with other signaling transduction pathways such as GATA proteins. Finally, the elucidation of the molecular basis of 3beta-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3beta-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3beta-HSD superfamily. Furthermore, several recent studies using type I and type II purified enzymes have elegantly further characterized structure-function relationships responsible for kinetic differences and coenzyme specificity.

show abstract

Section: Placentamentioning

confidence: 99%